1. Field of the Invention
The present invention relates to nobel hydantoin derivatives, salts thereof, intermediates therefor and having an optical activity, a process for the preparation of same, and medicines containing the derivative or salt as an effective ingredient to treat complications of diabetes.
The hydantoin derivatives and intermediates are shown by following formula.
Hydantoin derivatives ##STR4## wherein one of V and W is hydrogen and the other is a halogenomethyl group, 1H-tetrazol-5-yl radical, --COOR group,
in which R is hydrogen atom, an alkyl group, --(CH.sub.2 CH.sub.2 O)nCH.sub.3 group (n is an integer of 1 to 113) or substituted phenyl, ##STR5## group, in which R.sub.1 and R.sub.2 are same or different independently, each is hydrogen atom, an alkyl group, substituted phenyl or --(CH.sub.2 CH.sub.2 O)nCH.sub.3 group (n has the meaning as referred to) or R.sub.1 may form a heterocyclic ring together with R.sub.2 and nitrogen or oxygen atom, --CH.sub.2 OR.sub.3 group or ##STR6## group, in which R.sub.3 and R.sub.4 are same or different independently and each is hydrogen atom or an alkyl group, PA2 in which R.sub.6 is hydrogen atom, an alkyl group, --(CH.sub.2 CH.sub.2 O)nCH.sub.3 group (n is an integer of 1 to 113) or a substituted phenyl group, ##STR12## group, in which R.sub.1 and R.sub.2 are same or different independently, each is hydrogen atom, an alkyl group, substituted phenyl group, --(CH.sub.2 CH.sub.2 O)nCH.sub.3 group (n has the meaning as referred to) or R.sub.1 may form a heterocyclic ring together with R.sub.2 and nitrogen or oxygen atom, --CH.sub.2 OR.sub.3 group, ##STR13## group, in which R.sub.3 and R.sub.4 are same or different independently and each is hydrogen atom or an alkyl group, PA2 in which R is hydrogen atom, an alkyl group, --(CH.sub.2 CH.sub.2 O)nCH.sub.3 group (n is an integer of 1 to 113) or substituted phenyl, ##STR15## group, in which R.sub.1 and R.sub.2 are same or different independently, each is hydrogen atom, an alkyl group, substituted phenyl or --(CH.sub.2 CH.sub.2 O)nCH.sub.3 group (n has the meaning as referred to) or R.sub.1 may form a heterocyclic ring together with R.sub.2 and nitogen or oxygen atom, --CH.sub.2 OR.sub.3 group or ##STR16## group, in which R.sub.3 and R.sub.4 are same or different independently and each is hydrogen atom or an alkyl group,
X is oxygen or sulfur atom, and Y and Z are same or different independently and each is hydrogen atom, a halogen atom, alkyl group, alkoxy group, alkylmercapto group, nitro radical or --NHR.sub.5, in which R.sub.5 is hydrogen atom or an acyl group. PA1 X is oxygen or sulfur atom, Y" and Z" are same or different independently and each is hydrogen atom, a halogen atom, alkyl group, alkoxy group or alkylmercapto group, but there is no case of that one of V' and W' is hydrogen atom and the other is hydrogen atom or an alkyl group, when T is hydrogen substituted nitrogen atom and U is oxygen atom. PA1 X is oxygen or sulfur atom, and Y and Z are same or different independently and each is hydrogen atom, halogen atom, alkyl group, alkoxy group, alkylmercapto group, nitro radical or --NHR.sub.5 group, in which R.sub.5 is hydrogen atom or an acyl group,
Intermediates ##STR7## wherein Y' and Z' are same or different independently, each is hydrogen atom, a halogen atom or alkyl group.
2. Related Arts
Racemic 3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid derivatives having the chemical formula same with that for the intermediates have been known [Jap. Unexamined Pat. Appln. Gazette No. 200991/1986, "J. Med. Chem." Vol. 14, No. 8, pages 758-766 (1971) and "Liebigs Ann. Chem." pages 1552-1556 (1978)].
According to the process disclosed in said Japanese official gazette, the racemic derivatives (II-a) are prepared as shown in following reaction formula, by brominating 4-chromanone derivative (VI), treating with triethylamine to remove hydrogen bromide and to form a 4-chromenone derivative (VII), treating the derivative with trimethylsilylcyanide to give cyano compound, and treating with concentrated hydrochroric acid to cause hydrolysis of the cyanide. ##STR8## wherein Y' and Z' are same or different independently and each is hydrogen atom, a halogen atom or alkyl group.
However, this process can not always be said as preferable one, since it requires the expensive reagent of trimethylsilylcyanide.
According to the process described in said J. Med. Chem., the racemic derivatives (II-b) are prepared as shown in the following reaction formula, by condensationally reacting 4-chlorophenol with .alpha.-bromo-.gamma.-butylolactone to form the compound (VIII), oxidationally opening the ring with chromium trioxide to form the dicarboxylic acid (IX), and then treating with concentrated surfuric acid to cause a ring closure. ##STR9##
This process has also the disadvantage of that yield of the product is not so high of about 55 to 66%.
According to the process described in said Liebigs Ann. Chem., the racemic derivatives (II-c) are prepared as shown in the following reaction formula, by subjecting the monophenyl ester (X) of furmaric acid to Fries rearrangement, in the presence of aluminum chloride, and then causing a ring closure in sodium carbonate solution. ##STR10##
This process has disadvantages of that the synthetic yield of the raw material and yield of the Fries rearrangement reaction are low of about 30 to 52% and 16 to 50%, respectively.
Further, please note that each of the products obtained by such conventional processes has no optical activity and thus should be made into an optical active one, when the product is to be employed as the raw material to synthesize the hydantoin derivatives which are useful as the effective ingredient for medicines to prevent or cure the complications of diabetes.
Turning now to the diabetes, various studies have been made to seek compounds as effective ingredient for the medicine to prevent or cure the diabetes, which medicine can be administered in oral rout. As a result, various compounds of sulfonyl urea, mesooxalates, guanidine derivatives have been developed and various preparations containing one of the compounds have been marketed but each of them is of a mere symptomatic treating agent to a hyperglycoplasmia due to the diabetes. It has been known that there may be caused due to the biabetes specific chronic complications such as diabetic cataracts, diabetic neuropathy, diabetic retinopathy, diabetic nephrosis and the like but there is almost no effective agent for curing the complications and thus it may be said that no effective therapeutic system has been established.
Therefore, hitherto, various studies have also been made for developing an effective compound for curing such intractable diseases due to the diabetes but it is the fact that there is almost no success case. As one of the studies, there is a search on an anti- or inhibition substance to the enzymes of aldose reductase, since the enzyme reduces in vivo of human and other animals, aldoses such as glucose and galactose into corresponding polyols such as sorbitol and lactinol and it has been elucidated that said complications will appear when the polyols are accumulated at crystalline lens, peripheral nerve, kidney or the like in patients of diabetes or galactosemia ["Jap. J. Opthalmol." Vol. 20, page 399 (1976), "Int. Congr. Ser. Excerpta Med." Vol. 403, page 594 (1977), and "Metabolism" Vol. 28, page 456 (1979)].
Some of the inventors for this application have studied to find that following spiro-3-heteroazolidine derivatives and salts thereof are effective to the complications due to the diabetes (Jap. Pat. Appln. No. 41234/1985 early opened on Sept. 5, 1986 in Jap. Unexamined Pat. Appln. Gazette No. 200991/1986, which corresponding to U.S. patent application Ser. No. 835,823 and European Pat. Appln. No. 86301530.1, respectively). ##STR11## wherein T is sulfur atom or hydrogen substituted nitrogen atom, U is oxygen atom, sulfur atom or an amino radical, one of V' and W' is hydrogen atom or an alykl group and the other is hydrogen atom, 1H-tetrazol-5-yl radical, --COOR.sub.6,